Preparation of N-alkyl-N-pyridinyl-1H-indol-1-amines

ABSTRACT

The synthesis of memory enhancing, analgetic, and antidepressant N-alkyl-N-pyridinyl-1H-indol-1-amines is described.

The synthesis of memory enhancing, analgetic, and antidepressantN-alkyl-N-pyridinyl-1H-indol-1-amines 1, involving arylation of acompound of formula 2 ##STR1## by a halopyridine of formula 3 ##STR2##to provide an N-pyridinyl-1H-indol-1-amine of formula 4 ##STR3##followed by alkylation of 4 by a compound of formula 5

    R.sub.2 Z                                                  5

to yield an ultimate N-alkyl-N-pyridinyl-1H-indol-1-amine of formula 1##STR4## wherein R is hydrogen, loweralkyl or loweralkoxy; R₁ ishydrogen or loweralkyl; R₂ is loweralkyl; R₃ is hydrogen, loweralkyl orloweralkoxy; and m is 1 has been described. See, for example, U.S. Pat.No. 4,880,822 granted Nov. 14, 1989.

Applicants have now found that by starting with a 3-haloindole offormula 6 ##STR5## wherein R is as above and in addition istrifluoromethyl, R₁ is as above and m is as above and in addition is 2,prepared by halogenation of an indole of formula 7 ##STR6## wherein R(including trifluoromethyl), R₁ and m (including 2) are as above with ahalosuccinimide of formula 8 ##STR7## wherein X is bromo, chloro oriodo, aminating a 3-haloindole 6 to a 1-amino-3-haloindole 9 ##STR8##wherein R (including trifluoromethyl), R₁, X and m (including 2) are asabove, arylating a 1-aminoindole 9, so obtained, with a halopyridine 3wherein Y is a halogen to a 3-halo-N-pyridinylaminoindole 10 ##STR9##wherein R (including trifluoromethyl), R₁, R₃, X and m (including 2) areas above, alkylating an N-pyridinylaminoindole 10, so obtained, to anN-alkyl-3-halo-N-pyridinylaminoindole 11 ##STR10## wherein R (includingtrifluoromethyl), R₁, R₂, R₃, X and m (including 2) are as above, andfinally dehalogenating an N-alkyl-3-halo-N-pyridinylaminoindole 11, soobtained, an ultimate N-alkyl-N-pyridinyl-1H-indol-1-amine 1 wherein R(including trifluoromethyl), R₁, R₂, R₃ and m (including 2) are as aboveis obtained in high overall yield, even though a halo group isintroduced in the first step of the sequence and removed in the laststep to form the final product. In addition, costly, time consuming,yield reducing chromatographic separations and purifications are avoidedin the present process to prepare the desired pharmacological product.

Thus, the present invention relates to a process for the preparation ofmemory enhancing, analgetic and antidepressantN-alkyl-N-pyridinyl-1H-indole-1-amines. More particularly, the presentinvention relates to a process for the preparation of memory enhancing,analgetic and antidepressant N-alkyl-N-pyridinyl-1H-indol-1-amines offormula 1 involving the steps of halogenating a commercially availableor readily preparable indole 7 to a 3-haloindole 6, aminating a3-haloindole 6 to a 1-amino-3-haloindole 9, arylating a1-amino-3-haloindole 9 to a 3-halo-N-pyridinylaminoindole 10, alkylatinga 3-halo-N-pyridinylaminoindole 10 to anN-alkyl-3-halo-N-pyridinylaminoindole 11 and dehalogenating anN-alkyl-3-halo-N-pyridinylaminoindole 11 to anN-alkyl-N-pyridinylaminoindole 1, wherein R, R₁, R₂, X and M are asdescribed immediately above.

The present process is most particularly useful for the preparation ofN-alkyl-N-pyridinyl-1H-indole amines 1 wherein R is hydrogen; R₁ ishydrogen, R₂ is loweralkyl, R₃ is hydrogen and m is 1, and still mostparticularly wherein R₂ is n-propyl.

The halogenation of an indole 7 to a 3-haloindole 6 is accomplished bymethods known in the art, for example, by the use of anN-halosuccinimide 8 such as N-chlorosuccinamide in an aprotic dipolarsolvent, such as dimethylformamide at a reaction temperature of about10° to 18° C.

The amination is achieved by contacting a 3-haloindole 7 withhydroxylamine-O-sulfonic acid in a dipolar aprotic solvent in thepresence of a base or bases. Among dipolar aprotic solvents, there maybe mentioned dimethylacetamide, dimethylformamide,N-methyl-2-pyrrolidinone, dimethylsulfoxide and hexamethylphosphoramide,dimethylformamide being preferred. Among bases, there may be mentioned,alkali metal hydroxides and alkali metal carbonates, such as lithium,sodium and potassium hydroxides and lithium, sodium and potassiumcarbonates, respectively. Potassium hydroxide is the preferred base. Amixture of potassium hydroxide and potassium carbonate is the preferredmixture of bases. The amination reaction temperature is not narrowlycritical; the reaction proceeds at a satisfactory rate at a reducedtemperature of about -10° to about 20° C., an amination temperature ofabout 0° to about 10° being preferred.

The arylation is effected by contacting a 1-amino-3-haloindole 9 with ahalopyridine 3, as the free base or hydrohalide salt, preferably ahydrochloride salt, in a dipolar aprotic solvent such as, for example,dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, and N-methyl-2-pyrrolidinone, N-methyl-2-pyrrolidinonebeing preferred. The arylation proceeds at a reasonable rate at areaction temperature within the range of about 60° to 120° C., anarylation temperature of about 80° C. being preferred.

A 3-halo-N-pyridinylindolamine 10, is isolated as a benzoate salt,preferably the salicylate salt, prepared by treating a3-halo-N-pyridinylindolamine 10, with a benzoic acid, preferablysalicylic acid, in an alkyl alkanoate, preferably ethyl acetate, atambient temperature.

The alkylation is achieved by reacting a 3-halo-N-pyridinylindolamine10, with an alkyl halide 5, preferably an alkyl bromide, in a dipolaraprotic solvent (e.g., dimethylacetamide, dimethylformamide,dimethylsulfoxide, hexamethylphosphoramide, or N-methyl-2-pyrrolidinone)in the presence of a base (e.g., an alkali metal alkoxide, such as alithium, sodium or potassium alkoxide). Dimethylformamide is thepreferred solvent. Potassium tert-butoxide is the preferred base.

The alkylation is preferably performed at reduced temperatures withinthe range of about -10° to about 0° C. Alkylation temperatures withinthe range of about -20° to about 20° may be employed to effect theconversion.

When a benzoate salt of a 3-halo-N-pyridinylindolamine 10 is used in thealkylation step, the salt, preferably the salicylate salt, is convertedto the free base by treatment with an alkali metal hydroxide, such assodium hydroxide, in an aromatic solvent, such as toluene,, by ordinarymethods.

An N-alkyl-3-halopyridinylindolamine 11 is isolated as a hydrohalidesalt, preferably the hydrochloride salt, prepared by treating anN-alkyl-3-halopyridinylindolamine 11 with a hydrogen halide, preferablyhydrogen chloride, in an ethereal solvent, preferably diethyl ether.

The final step of the sequence, the dehalogenation of anN-alkyl-3-halo-N-pyridinylindolamine 11 to a pharmacologically activeN-alkyl-N-pyridinylindolamine 1 is accomplished by contacting anN-alkyl-3-halo-N-pyridinylindolamine 11 with formic acid in the presenceof a metal catalyst in an alkanol. Among alkanols, included aremethanol, ethanol, 1- and 2-propanols, 1,1-dimethylethanol and the like.2-Propanol is preferred. Included among metal catalysts arepalladium-on-carbon, Raney nickel, tetrakistriphenylphosphine palladium(0) and palladium acetate. Palladium-on-carbon is preferred.

The dehalogenation is carded out at elevated temperature, preferably thereflux temperature of the reaction medium, although it proceeds at areasonable rate at lower temperatures.

The dehalogenation may also be carded out on a hydrohalide salt,preferably the hydrochloride, of an N-alkyl-3-halo-N-pyridinylindolamine11. When a hydrohalide salt is used, a tertiary amine (e.g.,triethylamine, pyridine, picoline, lutidine, s-collidine, and the like)is employed to convert the salt to the free base.

An N-alkyl-N-pyridinylindolamine 11 is characterized as a hydrohalidesalt, preferably the hydrochloride salt, prepared by treating anindolamine 11 with a hydrohalic acid in an alkanol/ether, preferablymethanol/methyl tert-butyl ether, under ordinary conditions.

As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 8 carbon atoms such asmethyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl,4-heptyl, 2-octyl, and the like; the term "alkanol" refers to a compoundformed by a combination of an alkyl group and a hydroxy radical.Examples of alkanols are methanol, ethanol, 1- and 2-propanol,1,1-dimethylethanol, hexanol, octanol and the like. The term "alkanoicacid" refers to a compound formed by combination of a carboxyl groupwith a hydrogen atom or alkyl group. Examples of alkanoic acids areformic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid,hexanoic acid, octanoic acid and the like; the term "halogen" refers toa member of the family consisting of chlorine, bromine, iodine andfluorine. The term "lower" as applied to any of the aforementionedgroups refers to a group having a carbon skeleton containing up to andincluding 6 carbon atoms.

The following examples are for illustrative purposes only and are not tobe consumed as limiting the invention. All temperatures are given indegree centigrade (°C.).

EXAMPLE 1

Preparation of 3-chloroindole

To a 3 L round bottom flask equipped with a mechanical stirrer,thermometer and a Gooch tube was added sieve-dried dimethylformamide(1.2 L) and indole (200 g). The solution was stirred under an atmosphereof nitrogen and cooled to about 10° C. N-Chlorosuccinamide (216.6 g) wasadded via the Gooch tube at a rate such as to maintain a reactiontemperature of 10°-18° C. After the addition was complete, a secondcharge of N-chlorosuccinamide (34.2 g) was added. When the reaction wasfound to be >97% complete by high performance liquid chromatography, thereaction mixture was poured into a well-stirred, cold solution ofaqueous sodium bisulfite (5.2 L of 0.1% sodium bisulfite in water and640 g of ice). After about 15 min, the precipitate was collected andwashed with water (2×1 L). The filtrate was partitioned betweendichloromethane (1.3 L) and 0.1% aqueous sodium bisulfite solution (1L). The phases were separated and the aqueous solution was extractedwith dichloromethane (300 ml). The organic fractions were combined,washed with water (800 mL), dried over anhydrous magnesium sulfate,filtered and the filtrate was concentrated (at about 25° C. and about 50mm Hg). The residue was dried in a vacuum oven at 25° C. and about 125mm Hg for 2 to 4 hrs to yield 240.3 g (92.9%) of product, 3-chloroindole(91.6% pure).

EXAMPLE 2

Preparation of 3-chloro-1H-indol-1-amine

To a 12 L round bottom flask equipped with a mechanical stirrer,thermometer and a Gooch tube was added sieve-dried dimethylformamide(2.8 L), 3-chloroindole (240 g, 91.6% pure), milled potassium carbonate(200.4 g), milled potassium hydroxide (574.3 g, 85% pure) anddimethylformamide (900 mL) at -2° to 5° C. The reaction mixture wascooled to about 0° C. and hydroxylamine-O-sulfonic acid (338.2 g, 97%pure) was added portionwise via the Gooch tube over a period of about 4hrs, maintaining the reaction temperature at about 0° C. When thereaction was >95% complete (by high performance liquid chromatography),the reaction mixture was poured into a well-stirred, cold mixture ofwater (18 L and 3.6 kg ice) and toluene (2.4 L). After about 5 mins, thephases were separated and the aqueous phase was extracted with toluene(1×2.4 L and 1×1 L). The organic fractions were combined and filteredthrough Celite. The filtrate was concentrated under reduced pressure(about 50 mm Hg) at about 60° C. to yield 245 g (86%) of product.

EXAMPLE 3

Preparation of 3-chloro-N-4-pyridinyl-1H-indol-1-amine salicylate

A mixture of 3-chloro-1H-indol-1-amine (100 g), 1-methyl-2-pyrrolidinone(490 mL) and 4-chloropyridine hydrochloride (75.9 g, 96.2% pure) washeated at about 80° C., with stirring, under nitrogen, for 2 hrs. Whenthe reaction was 88-89% complete, the reaction mixture was cooled toroom temperature and poured into a well-stirred mixture of 5% sodiumhydroxide solution (1.2 L) and toluene (800 mL). The mixture was stirredfor 15 mins, filtered through Celite, and the phases of the filtratewere separated. The aqueous phase was extracted with toluene (1×400 mLand 1×200 mL). The organic fractions were combined and washed with water(800 mL). The emulsion was filtered through Celite and the phases wereseparated. The organic phase was dried over anhydrous potassiumcarbonate, filtered and the filtrate was concentrated at 50°-60° C.under reduced pressure (about 50 mm Hg) to provide 131.5 g of product asthe free base.

The product, 3-chloro-N-4-pyridinyl-1H-indol-1-amine, was dissolved inethyl acetate (745 mL) and filtered. The filtrate was added to a 2 Lround bottom flask equipped with a mechanical stirrer. Salicylic acid(80.7 g) was added, with stirring, under a nitrogen atmosphere at roomtemperature. After stirring the mixture at room temperature for 2 hrs,the precipitate was collected and the filter cake was washed with cold(0°-5° C.) ethyl acetate (30 mL) and dried at 68°-70° C. (125 mm Hg) for16 hrs to give 90.0 g (48.4%) of product,3-chloro-N-4-pyridinyl-1H-indol-1-amine salicylate (99% pure), mp of185°-186° C.

EXAMPLE 4

Preparation of 3-chloro-N-propyl-N-4-pyridinyl-1H-indol-1-aminehydrochloride

A solution of 3-chloro-N-4-pyridinyl-1H-indol-1-amine salicylate (10 g),toluene (100 mL) and 5% aqueous sodium hydroxide solution (100 mL) wasfiltered through Celite and the phases were separated. The aqueous phasewas extracted with toluene (50 mL), and the combined organic phase waswashed with water (75 mL), dried over anhydrous potassium carbonate,filtered and the filtrate was concentrated (50° C. bath, 50 mm Hg) togive the free base, 3-chloro-N-4-pyridinyl-1H-indol-1-amine.

To a 125 mL round bottom flask equipped with a mechanical stirrer,thermometer and a Gooch tube was added sieve-dried dimethylformamide (36mL) and 3-chloro-N-4-pyridinyl-1H-indol-1-amine (4.5 g). The solutionwas cooled to about -10° C., with stirring, under a nitrogen atmosphere.Potassium-τ-butoxide (2.29 g) was added via the Gooch tube at a ratesuch as to maintain a reaction temperature of about -10° C. After theaddition was complete, the mixture was allowed to warm to about 0° C.and age for about 1 hr. The Gooch tube was replaced with a droppingfunnel and a solution of 1-bromopropane (2.96 g) in drydimethylformamide (8.8 mL) was added at a rate such as to maintain areaction temperature of about 0° C. When the reaction was 98% complete,the reaction mixture was poured into a stirred mixture of cold water (72mL) and ethyl acetate (30 mL). The phases were separated and the aqueousphase was extracted with ethyl acetate (2×30 mL). The combined organicphase was washed with water (50 mL), dried over anhydrous magnesiumsulfate, filtered and the filtrate was concentrated (at about 40° C.bath temperature and about 50 mm Hg) to yield 5.1 g (96.2%) of productas the free base (88.6% pure).

To a 4 g sample of product,3-chloro-N-propyl-N-4-pyridinyl-1H-indol-1-amine, dissolved in anhydrousether (60 mL) in a 125 mL-round bottom flask equipped with a mechanicalstirrer, thermometer and dropping funnel, was added slowly an etherealsolution saturated with hydrogen chloride (6 mL) at room temperature,under a nitrogen atmosphere, with stirring. After about 0.5 hrs at roomtemperature, the precipitate was collected, washed with anhydrous ether(15 mL) and dried to yield 3.95 g (87.6%) of product.

EXAMPLE 5

Preparation of N-propyl-N-4-pyridinyl-1H-indol-1-amine hydrochloride

To a mixture of 3-chloro-N-propyl-N-4-pyridinyl-1H-indol-1-aminehydrochloride (500 mg), triethylamine (408 mg) and 5%palladium-on-carbon (34.7 mg) in 2-propanol (2.5 mL) was added, under anitrogen purge, 98% formic acid (0.068 mL) via a syringe, with stirring.After the addition was complete, the reaction mixture was heated toreflux. Additional amounts of 5% palladium-on-carbon (104 mg),triethylamine (0.22 mL) and formic acid (0.028 mL) were added over 7.5hrs in 3 portions. The mixture was cooled to room temperature, filteredthrough Celite and the filter cake was washed with 2-propanol (about 30mL). The filtrate was concentrated under reduced pressure (50 mm Hg) andthe residue partitioned between toluene (8 mL) and 5% aqueous sodiumhydroxide solution (8 mL). The aqueous phase was separated and extractedwith toluene (5 mL). The organic fractions were combined, washed withwater (10 mL), dried over anhydrous magnesium sulfate and filtered. Thefiltrate was concentrated under reduced pressure (50 mm Hg) at 60° C. toyield 310 mg (79.5%) of the product, as the free base, (99% pure).

To a 25 mL round bottom flask equipped with a mechanical stirrer,thermometer and condenser was addedN-propyl-N-4-pyridinyl-1H-indol-1-amine (2.1 g), methanol (2 mL), and36-37% hydrochloric acid (0.66 mL), with stirring, at room temperature.The reaction mixture was seeded with product prepared previously and,after 5 mins, methyl-t-butyl ether (8.0 mL) was added, with stirring.The reaction mixture was allowed to cool to room temperature, thencooled to about 0° C. The precipitate was collected and the filter cakewas washed with cold 1:4 methanol/methyl-t-butyl ether (2 mL), followedby methyl-t-butyl ether (6 mL) and dried at 85° C. (25 inches ofmercury) to yield 2.07 g (88.6%) of product.

The determination of the purity of the reactants and the products of theexamples was determined in a Perkin-Elmer 410/Kratos Spectroflow 783high performance liquid chromatograph using a Phenomenex Bondclone 10C18(3.9×300 mm) column with a mobile phase of 50:50 acetonitrile/0.1Naqueous ammonium formate solution at a flow rate of 1.5 mL/min. withdetection at 255 nm. Samples were prepared in acetonitrile, filtered andapplied to the column.

We claim:
 1. A process for the preparation of a compound of the formula##STR11## wherein R is hydrogen, loweralkyl, loweralkoxy ortrifluoromethyl; R₁ is hydrogen or loweralkyl; R₂ is loweralkyl; R₃ ishydrogen, loweralkyl, loweralkoxy or trifluoromethyl; and m is 1 or 2,which comprises the steps of:(a) reacting a compound of the formula##STR12## wherein R, R₁ and m are as above with a compound of theformula ##STR13## wherein X is bromo, chloro or iodo to provide acompound of the formula ##STR14## wherein R, R₁, X and m are as above;(b) reacting the compound obtained in step (a) with a compound of theformula

    H.sub.2 NOSO.sub.3 H

to provide a compound of the formula ##STR15## wherein R, R₁, X and mare as above; (c) reacting a compound obtained in step (b) with acompound of the formula ##STR16## wherein R₃ is as above and Y ischloro, bromo or iodo to provide a compound of the formula ##STR17##wherein R, R₁, R₃, X and m are as above; (d) reacting a compoundobtained in step (c) with a compound of the formula

    R.sub.2 Z

wherein R₂ is as above and Z is bromo or chloro to provide a compound ofthe formula ##STR18## wherein R, R₁, R₂, R₃, X and m are as above; (e)reacting a compound obtained in step (d) with formic acid in thepresence of a metal catalyst; and (f) isolating the product.
 2. Aprocess according to claim 1 wherein R is hydrogen; R₁ is hydrogen; R₂is loweralkyl; R₃ is hydrogen and m is
 1. 3. The process according toclaim 2 wherein R₂ is n-propyl.
 4. A process according to claim 1wherein X and Y are chloro and Z is bromo.
 5. A process according toclaim 1 wherein a solvent is employed in step (a).
 6. A processaccording to claim 5 wherein the solvent is a dipolar aprotic solvent.7. The process according to claim 6 wherein the dipolar aprotic solventis dimethylformamide.
 8. A process according to claim 1 wherein a baseor a mixture of bases is employed in step (b).
 9. A process according toclaim 8 wherein the base is an alkali metal hydroxide.
 10. The processaccording to claim 9 wherein the alkali metal hydroxide is potassiumhydroxide.
 11. A process according to claim 8 wherein the mixture ofbases is an alkali metal hydroxide and an alkali metal carbonate. 12.The process according to claim 11 wherein the alkali metal hydroxide ispotassium hydroxide and the alkali metal carbonate is potassiumcarbonate.
 13. A process according to claim 1 wherein a solvent isemployed in step (b).
 14. A process according to claim 13 wherein thesolvent is a dipolar aprotic solvent.
 15. The process according to claim14 wherein the dipolar aprotic solvent is dimethylformamide.
 16. Aprocess according to claim 1 wherein a solvent is employed in step (c).17. A process according to claim 16 wherein the solvent is a dipolaraprotic solvent.
 18. The process according to claim 17 wherein thedipolar aprotic solvent is 1-methyl-2-pyrrolidinone.
 19. A processaccording to claim 1 wherein the product of step (c) is treated with abenzoic acid in a loweralkyl alkanoate to form a benzoate salt thereof.20. The process according to claim 19 wherein the benzoic acid issalicylic acid and the loweralkyl alkanoate is ethyl acetate.
 21. Aprocess according to claim 1 wherein a solvent is employed in step (d).22. A process according to claim 21 wherein the solvent is a dipolaraprotic solvent.
 23. The process according to claim 22 wherein thedipolar aprotic solvent is dimethylformamide.
 24. A process according toclaim 1 wherein a benzoate salt of the compound obtained in step (c) isemployed in step (d).
 25. A process according to claim 24 wherein thebenzoate salt is a salicylate salt.
 26. A process according to claim 24wherein the benzoate salt is converted to the compound obtained in step(c).
 27. A process according to claim 26 wherein an aromatic solvent andan aqueous solution of an alkali metal hydroxide are employed.
 28. Theprocess according to claim 27 wherein the aromatic solvent is tolueneand the alkali metal hydroxide is sodium hydroxide.
 29. A processaccording to claim 1 wherein a base is employed in step (d).
 30. Aprocess according to claim 29 wherein the base is an alkali metalalkoxide.
 31. The process according to claim 30 wherein the alkali metalalkoxide is potassium tert-butoxide.
 32. A process according to claim 1wherein the compound obtained in step (d) is treated with a hydrohalidein an ethereal solvent to form a hydrohalide salt thereof.
 33. Theprocess according to claim 32 wherein the hydrohalide is hydrogenchloride and the ethereal solvent is diethyl ether.
 34. A processaccording to claim 1 wherein the metal catalyst employed in step (e) isselected from the group consisting of palladium-on-carbon, Raney nickel,tetrakistriphenylphosphine palladium (0), and palladium acetate.
 35. Theprocess according to claim 34 wherein the palladium-on-carbon is 5%palladium-on-carbon.
 36. A process according to claim 1 wherein asolvent is employed in step (e).
 37. A process according to claim 36wherein the solvent is an alkanol.
 38. The process according to claim 37wherein the alkanol is 2-propanol.
 39. A process according to claim 1wherein a hydrohalide salt of a compound obtained in step (d) isemployed in step (e).
 40. The process according to claim 39 wherein thehydrohalide salt is the hydrochloride salt.
 41. A process according toclaim 1 wherein a base is employed in step (e) when a hydrohalide saltof the compound obtained in step (d) is used.
 42. A process according toclaim 41 wherein the base is a tertiary amine.
 43. The process accordingto claim 42 wherein the tertiary amine is triethylamine.
 44. The processaccording to claim 41 wherein the hydrohalide salt is the hydrochloridesalt.
 45. A process according to claim 1 wherein the compound obtainedin step (e) is treated with a hydrohalic acid in an alkanol to form ahydrohalide salt thereof.
 46. The process according to claim 45 whereinthe hydrohalic acid is hydrochloric acid.
 47. The process according toclaim 45 wherein the alkanol is methanol.
 48. A process according toclaim 1 wherein the reaction of step (a) is performed at a temperatureof from about 10° to about 18° C.
 49. A process according to claim 1wherein the reaction of step (b) is performed from about -10° to 20° C.50. The process according to claim 49 wherein the reaction of step (b)is performed at about 0° C. to 10° C.
 51. A process according to claim 1wherein the reaction of step (c) is performed within the range of about60° to about 120° C.
 52. The process according to claim 51 wherein thereaction is performed at about 80° C.
 53. A process according to claim 1wherein the reaction of step (d) is performed within the range of about-20° to about 20° C.
 54. The process according to claim 53 wherein thereaction temperature is about -10° C. to about 0° C.
 55. A processaccording to claim 1 wherein the reaction of step (e) is performed at atemperature of about the reflux temperature of the reaction medium.